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Peer-reviewedCC BY 4.0Reviews in Cardiovascular Medicine

Exogenous Hydrogen Sulfide Promotes FAM134B-Mediated Endoplasmic Reticulum Autophagy and Inhibits Cell Aging by PERK–eIF2α and Improves Homocysteinemic Hypertensive-Induced Myocardial Fibrosis

  • Chenlong Luo1
  • Yaling Li1
  • Jianghe Jiang1
  • Yan Shi2
  • Liangui Nie1
  • Zhixiong Wu3
  • Yiding Luo4
  • Chun Chu2
  • Jun Yang1,2,5,6
6 affiliations
  1. 1The First Affiliated Hospital of Department of Cardiology, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
  2. 2The Second Affiliated Hospital of Department of Pharmacy, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
  3. 3Zhuzhou Central Hospital of Department of Cardiology, 412000 Zhuzhou, Hunan, China
  4. 4Department of Clinical Medicine, Changsha Medical University, 410219 Changsha, Hunan, China
  5. 5Hunan Provincial Key Laboratory of Multi-omics And Artificial Intelligence of Cardiovascular Diseases, University of South China, 421001 Hengyang, Hunan, China
  6. 6Clinical Research Center for Myocardial Injury in Hunan Province, 421001 Hengyang, Hunan, China
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Abstract

Background:: Hyperhomocysteinemia (HHCY) is a major cardiovascular risk factor closely associated with hypertension, myocardial fibrosis, and cardiac dysfunction; however, the underlying cellular mechanisms remain incompletely understood. Hydrogen sulfide (H2S) has emerged as an important cardioprotective gasotransmitter, yet the role of H2S in regulating endoplasmic reticulum (ER) stress and ER-phagy in HHCY-related cardiac remodeling remains unknown.

Methods:: Therefore, this study aimed to investigate the effects of exogenous H2S in a rat model of hyperhomocysteinemic hypertension and in H9c2 cells exposed to homocysteine and angiotensin II.

Results:: HHCY markedly increased blood pressure, exacerbated myocardial fibrosis, and promoted cardiomyocyte senescence, accompanied by activation of ER stress signaling and suppression of ER-phagy. Administration of H2S significantly alleviated these pathological changes, as evidenced by improved hemodynamic parameters, reduced collagen deposition, and decreased expression of senescence-associated markers. Mechanistically, H2S treatment attenuated activation of the Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK)–Eukaryotic Initiation Factor 2α (eIF2α) pathway and enhanced Family with Sequence Similarity 134, Member B (FAM134B)-dependent ER-phagy, as indicated by increased LC3-II accumulation and augmented colocalization of FAM134B with LC3. Furthermore, silencing FAM134B substantially blunted the ability of H2S to restore ER-phagy and suppress cellular senescence, supporting a critical role for FAM134B in mediating the protective effects of H2S.

Conclusions:: These findings demonstrate that exogenous H2S mitigates HHCY-induced myocardial remodeling, in part, by dampening PERK–eIF2α-associated ER stress and promoting FAM134B-mediated ER-phagy. This study provides mechanistic insight into the cardioprotective actions of H2S in hyperhomocysteinemic cardiac injury and identifies ER-phagy as a potential therapeutic target.

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Cite

BibTeXRIS
BibTeX
@article{luo2026exogenous,
  title = {{Exogenous Hydrogen Sulfide Promotes FAM134B-Mediated Endoplasmic Reticulum Autophagy and Inhibits Cell Aging by PERK–eIF2α and Improves Homocysteinemic Hypertensive-Induced Myocardial Fibrosis}},
  author = {Chenlong Luo and Yaling Li and Jianghe Jiang and Yan Shi and Liangui Nie and Zhixiong Wu and Yiding Luo and Chun Chu and Jun Yang},
  journal = {Reviews in Cardiovascular Medicine},
  year = {2026},
  month = oct,
  doi = {10.31083/rcm51893},
  url = {https://doi.org/10.31083/rcm51893},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Exogenous Hydrogen Sulfide Promotes FAM134B-Mediated Endoplasmic Reticulum Autophagy and Inhibits Cell Aging by PERK–eIF2α and Improves Homocysteinemic Hypertensive-Induced Myocardial Fibrosis
AU  - Chenlong Luo
AU  - Yaling Li
AU  - Jianghe Jiang
AU  - Yan Shi
AU  - Liangui Nie
AU  - Zhixiong Wu
AU  - Yiding Luo
AU  - Chun Chu
AU  - Jun Yang
PY  - 2026
DA  - 2026/10/14
JO  - Reviews in Cardiovascular Medicine
DO  - 10.31083/rcm51893
UR  - https://doi.org/10.31083/rcm51893
AB  - Background:: Hyperhomocysteinemia (HHCY) is a major cardiovascular risk factor closely associated with hypertension, myocardial fibrosis, and cardiac dysfunction; however, the underlying cellular mechanisms remain incompletely understood. Hydrogen sulfide (H2S) has emerged as an important cardioprotective gasotransmitter, yet the role of H2S in regulating endoplasmic reticulum (ER) stress and ER-phagy in HHCY-related cardiac remodeling remains unknown.  Methods:: Therefore, this study aimed to investigate the effects of exogenous H2S in a rat model of hyperhomocysteinemic hypertension and in H9c2 cells exposed to homocysteine and angiotensin II.  Results:: HHCY markedly increased blood pressure, exacerbated myocardial fibrosis, and promoted cardiomyocyte senescence, accompanied by activation of ER stress signaling and suppression of ER-phagy. Administration of H2S significantly alleviated these pathological changes, as evidenced by improved hemodynamic parameters, reduced collagen deposition, and decreased expression of senescence-associated markers. Mechanistically, H2S treatment attenuated activation of the Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK)–Eukaryotic Initiation Factor 2α (eIF2α) pathway and enhanced Family with Sequence Similarity 134, Member B (FAM134B)-dependent ER-phagy, as indicated by increased LC3-II accumulation and augmented colocalization of FAM134B with LC3. Furthermore, silencing FAM134B substantially blunted the ability of H2S to restore ER-phagy and suppress cellular senescence, supporting a critical role for FAM134B in mediating the protective effects of H2S.  Conclusions:: These findings demonstrate that exogenous H2S mitigates HHCY-induced myocardial remodeling, in part, by dampening PERK–eIF2α-associated ER stress and promoting FAM134B-mediated ER-phagy. This study provides mechanistic insight into the cardioprotective actions of H2S in hyperhomocysteinemic cardiac injury and identifies ER-phagy as a potential therapeutic target.
SN  - 1530-6550
SN  - 2153-8174
ER  -